Paul E. Keck

Comorbidity of fibromyalgia with medical and psychiatric disorders

PURPOSE Patients with fibromyalgia have been reported to display high rates of several concomitant medical and psychiatric disorders, including migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. To test further these and other possible associations, we assessed the personal and family histories of a broad range of medical and psychiatric disorders in patients with fibromyalgia. PATIENTS AND METHODS Subjects were 33 women (mean age 42.1 years) who each met American College of Rheumatology criteria for fibromyalgia and presented to a rheumatologist at a tertiary referral center. They received the Structured Clinical Interview for DSM-III-R (SCID); a supplemental interview, in SCID format, for other medical and psychiatric disorders, including migraine, irritable bowel syndrome, and chronic fatigue syndrome; and an interview for family history of medical and psychiatric disorders. RESULTS Patients with fibromyalgia displayed high lifetime rates of migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. They also exhibited high rates of familial major mood disorder. CONCLUSIONS The finding that migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder are frequently comorbid with fibromyalgia is consistent with the hypothesis that these various disorders may share a common physiologic abnormality.

The Stanley Foundation Bipolar Treatment Outcome Network: II. Demographics and illness characteristics of the first 261 patients

BACKGROUND Since recent NIMH Bipolar Disorder Workshops highlighted the dearth of longitudinal and controlled studies of bipolar illness, the Stanley Foundation Bipolar Network (SFBN) has recruited a large cohort of patients with bipolar disorder to begin to address these issues. This report describes the demographics and course of illness characteristics of this study population. METHODS The first 261 outpatients to be diagnosed by the Structured Clinical Interview for DSM-IV (SCID) and complete a detailed patient and a brief clinician questionnaire are described. All patients met DSM-IV criteria for bipolar I (n=211), bipolar II (n=42), or NOS (n=5) or schizoaffective (n=3), bipolar type. Chi-square and t-tests were used to examine statistically significant associations among important demographic and descriptive items. RESULTS The general demographic and illness characteristics were similar to those in many bipolar clinical samples and not dissimilar from those reported in epidemiological surveys. The majority of patients had been hospitalized, with almost half reporting a worsening of illness over time, and two-thirds were not asymptomatic between episodes. First treatment for patients had been delayed by an average of 10 years from illness onset (by SCID). Almost a third of patients had attempted suicide at least once, and 30% reported current suicidal ideation at study entry. A total of 62% reported moderate to severe impact of the illness on occupational functioning. Early onset bipolar illness (< or =17 years old) was associated with increased frequency of mood switches, worsening course of illness, and history of early abuse (physical, verbal, or sexual). CONCLUSION The SFBN represents a sample of predominantly BP I patients largely recruited from the community who will be followed in detail longitudinally, participate in clinical trials, and thus help advance our understanding and treatment of this life-threatening medical disorder. While there is a broad range of illness characteristics and severity, the majority of patients have been severely impacted by their illness despite the availability of multiple conventional treatment approaches in the community. These data further underscore the need for development of new and earlier treatment interventions. LIMITATION The SFBN population is limited by the lack of random selection and represents a cohort willing to be treated and followed intensively in academic tertiary referral centers. While its characteristics are similar to many clinical study populations, the generalizability to non-clinic populations remains uncertain.

Early physical and sexual abuse associated with an adverse course of bipolar illness

BACKGROUND There is growing awareness of the association between physical and sexual abuse and subsequent development of psychopathology, but little is known, however, about their relationship to the longitudinal course of bipolar disorder. METHODS We evaluated 631 outpatients with bipolar I or II disorder for general demographics, a history of physical or sexual abuse as a child or adolescent, course of illness variables, and prior suicide attempts, as well as SCID-derived Axis I and patient endorsed Axis II comorbidity. RESULTS Those who endorsed a history of child or adolescent physical or sexual abuse, compared with those who did not, had a history of an earlier onset of bipolar illness, an increased number of Axis I, II, and III comorbid disorders, including drug and alcohol abuse, faster cycling frequencies, a higher rate of suicide attempts, and more psychosocial stressors occurring before the first and most recent affective episode. The retrospectively reported associations of early abuse with a more severe course of illness were validated prospectively. CONCLUSIONS Greater appreciation of the association of early traumatic experiences and an adverse course of bipolar illness should lead to preventive and early intervention approaches that may lessen the associated risk of a poor outcome.

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia

PURPOSE To assess the efficacy of fluoxetine in the treatment of patients with fibromyalgia. SUBJECTS AND METHODS Sixty outpatients (all women, aged 21-71 years) with fibromyalgia were randomly assigned to receive fluoxetine (10-80 mg/d) or placebo for 12 weeks in a double-blind, parallel-group, flexible-dose study. The primary outcome measures were the Fibromyalgia Impact Questionnaire total score (score range, 0 [no impact] to 80) and pain score (score range, 0-10). Secondary measures included the McGill Pain Questionnaire, change in the number of tender points, and total myalgic score. RESULTS In the intent-to-treat analysis, women who received fluoxetine (mean [+/- SD] dose, 45 +/- 25 mg/d) had significant (P = 0.005) improvement in the Fibromyalgia Impact Questionnaire total score compared with those who received placebo, with a difference of -12 (95% confidence interval [CI]: -19 to -4). They also had significant (P = 0.002) improvement in the Fibromyalgia Impact Questionnaire pain score (difference, -2.2 [95% CI: -3.6 to -0.9]), as well as in the Fibromyalgia Impact Questionnaire fatigue (P = 0.05) and depression (P = 0.01) scores and the McGill Pain Questionnaire (P = 0.01), when compared with subjects who received placebo. Although counts for the number of tender points and total myalgic scores improved more in the fluoxetine group than in the placebo group, these differences were not statistically significant. CONCLUSIONS In a 12-week, flexible-dose, placebo-controlled trial, fluoxetine was found to be effective on most outcome measures and generally well tolerated in women with fibromyalgia.

Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder.

Bipolar affective disorder (BPAD) is suspected to arise in part from malfunctions of the circadian system, a system that enables adaptation to a daily and seasonally cycling environment. Genetic variations altering functions of genes involved with the input to the circadian clock, in the molecular feedback loops constituting the circadian oscillatory mechanism itself, or in the regulatory output systems could influence BPAD as a result. Several human circadian system genes have been identified and localized recently, and a comparison with linkage hotspots for BPAD has revealed some correspondences. We have assessed evidence for linkage and association involving polymorphisms in 10 circadian clock genes (ARNTL, CLOCK, CRY2, CSNK1ε, DBP, GSK3β, NPAS2, PER1, PER2, and PER3) to BPAD. Linkage analysis in 52 affected families showed suggestive evidence for linkage to CSNK1ε. This finding was not substantiated in the association study. Fifty‐two SNPs in 10 clock genes were genotyped in 185 parent proband triads. Single SNP TDT analyses showed no evidence for association to BPAD. However, more powerful haplotype analyses suggest two candidates deserving further studies. Haplotypes in ARNTL and PER3 were found to be significantly associated with BPAD via single‐gene permutation tests (PG = 0.025 and 0.008, respectively). The most suggestive haplotypes in PER3 showed a Bonferroni‐corrected P‐value of PGC = 0.07. These two genes have previously been implicated in circadian rhythm sleep disorders and affective disorders. With correction for the number of genes considered and tests conducted, these data do not provide statistically significant evidence for association. However, the trends for ARNTL and PER3 are suggestive of their involvement in bipolar disorder and warrant further study in a larger sample.

Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder : a 4-week placebo-controlled trial

Abstract A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S, BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (≥30% reduction) and the CGI improvement (score ≤2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden.

Early-Onset Bipolar Disorder and Treatment Delay Are Risk Factors for Poor Outcome in Adulthood

OBJECTIVE We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood. METHOD 529 adult outpatients with a mean age of 42 years, who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years. RESULTS Fifty percent of patients had illness onset in childhood (<13 years of age) or adolescence (13-18 years of age). In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P<.05) greater severity of depression and mania, greater number of episodes, more days depressed, more days of ultradian cycling, and fewer days euthymic. After 4 years, the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset (P<.05). The delays to first treatment correlated inversely with age at onset of illness. Independently, delay to first treatment was associated with more time depressed, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic (all P<.05). CONCLUSIONS These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment. Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospectively in adults. These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents. It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood.

Differences and similarities in mixed and pure mania

The aim of this study was to examine the relationship between mixed and pure mania using both narrow (DSM-III-R) and broad (Cincinnati) operational diagnostic criteria to define mixed mania regarding the degree of associated depression. Hospitalized patients aged > or = 12 years and meeting DSM-III-R criteria for bipolar disorder, manic or mixed, were compared regarding demographics, phenomenology, course of illness, comorbidity, family history, and short-term outcome. Seventy-one patients were recruited during a 1-year period. Twenty-four patients (34%) met DSM-III-R criteria for mixed bipolar disorder; 28 (40%) met the broader definition (which required three associated depressive symptoms rather than full syndromal DSM-III-R depression). Compared with pure manic patients, DSM-III-R mixed patients had significantly more depressive symptoms, were more likely to be female, experienced more prior mixed episodes, displayed higher rates of comorbid obsessive-compulsive disorder, and had longer hospitalizations. However, when mixed mania was defined more broadly, differences in gender and hospitalization length were lost. Also, regardless of the definition used, mixed and pure manic patients were similar on most other variables assessed. We conclude that mixed and pure mania differ in some respects but have many similarities, especially when mixed mania is defined by lesser degrees of depression. The use of dimensional rather than categoric systems to describe the degree of associated depression may be a more meaningful method of classifying mania.

High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure

BACKGROUND We assessed the prevalence of thyroperoxidase antibodies (TPO-Abs) and thyroid failure in outpatients with bipolar disorder compared with two control groups. METHODS The TPO-Abs of outpatients with DSM-IV bipolar disorder (n = 226), a population control group (n = 252), and psychiatric inpatients of any diagnosis (n = 3190) were measured. Thyroid failure was defined as a raised thyroid stimulating hormone level, previously diagnosed hypothyroidism, or both. Subjects were compared with attention to age, gender, and exposure to lithium. RESULTS The TPO-Abs were more prevalent in bipolar patients (28%) than population and psychiatric controls (3-18%). The presence of TPO-Abs in bipolar patients was associated with thyroid failure, but not with age, gender, mood state, rapid cycling, or lithium exposure. Thyroid failure was present in 17% of bipolar patients and more prevalent in women. It was associated with lithium exposure, especially in the presence of TPO-Abs, but not with current rapid cycling, although an association may have been masked by thyroid hormone replacement. CONCLUSIONS Thyroid autoimmunity was highly prevalent in this sample of outpatients with bipolar disorder and not associated with lithium treatment. These variables appear to be independent risk factors for the development of hypothyroidism, especially in women with bipolar disorder.